Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA.
J Exp Med. 2017 Sep 4;214(9):2649-2670. doi: 10.1084/jem.20161900. Epub 2017 Aug 9.
In this study, we show that mice lacking high-molecular-weight kininogen (HK) were resistant to lipopolysaccharide (LPS)-induced mortality and had significantly reduced circulating LPS levels. Replenishment of HK-deficient mice with human HK recovered the LPS levels and rendered the mice susceptible to LPS-induced mortality. Binding of HK to LPS occurred through the O-polysaccharide/core oligosaccharide, consistent with the ability to bind LPS from , , , and different strains. Binding of LPS induced plasma HK cleavage to the two-chain form (HKa, containing a heavy chain [HC] and a light chain [LC]) and bradykinin. Both HKa and the LC, but not the HC, could disaggregate LPS. The light chain bound LPS with high affinity ( = 1.52 × 10 M) through a binding site in domain 5 (DHG15). A monoclonal antibody against D5 significantly reduced LPS-induced mortality and circulating LPS levels in wild-type mice. Thus, HK, as a major LPS carrier in circulation, plays an essential role in endotoxemia.
在这项研究中，我们表明缺乏高分子量激肽原（HK）的小鼠对脂多糖（LPS）诱导的死亡率具有抗性，并且循环 LPS 水平显著降低。用人类 HK 补充 HK 缺乏的小鼠可恢复 LPS 水平，并使小鼠易受 LPS 诱导的死亡率影响。HK 与 LPS 的结合通过 O-多糖/核心寡糖发生，这与结合来自 、 、 和不同 株的 LPS 的能力一致。LPS 结合诱导血浆 HK 裂解为双链形式（HKa，包含重链 [HC] 和轻链 [LC]）和缓激肽。HKa 和 LC 都可以使 LPS 解聚，而 HC 则不能。LC 通过结构域 5 中的结合位点（DHG15）以高亲和力（ = 1.52 × 10 M）结合 LPS。针对 D5 的单克隆抗体可显著降低野生型小鼠中 LPS 诱导的死亡率和循环 LPS 水平。因此，作为循环中主要的 LPS 载体，HK 在败血症中发挥着重要作用。
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